Enteric coated formulation for bisphosphonic acids and salts thereof

ABSTRACT

Pharmaceutical compositions and methods of using the composition are provided. The pharmaceutical composition comprises an inert core surrounded by an active coating containing one or more bisphosphonic acids or salts thereof, a seal coating surrounding the active coating and an enteric coating surrounding the seal coating. Alendronic acid and alendronate sodium trihydrate are the preferred active ingredients. The composition may be provided in the form of pellets in a capsule or Peltabs. The invention further provides methods for the treatment of disorders caused by the abnormal dissolution or deposition of calcium salts using the inventive compositions.

This application is a continuation of U.S. application Ser. No.09/669,635, filed Sep. 26, 2000 Now U.S. Pat. No. 6,676,955, whichclaims priority to Indian Application Nos. 710/BOM/99 and 23/BOM-WTO/99(709/BOM/99), both of which were filed on Oct. 10, 1999, each of whichis incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a pharmaceutical composition, a processof preparing the pharmaceutical composition and a method of using thepharmaceutical composition. Specifically, the invention provides apharmaceutical composition containing bisphosphonic acids or saltsthereof for use in the treatment of osteoporosis and other disorderscaused by the abnormal dissolution or deposition of calcium salts.

2. Background of the Invention

Methods of preparing bisphosphonic acids are set forth in U.S. Pat. No.3,962,432; U.S. Pat. No. 4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat.No. 4,327,039; U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,621,077; U.S.Pat. No. 4,624,947; U.S. Pat. No. 4,746,654; U.S. Pat. No. 4,922,007;and EPO Patent Pub. No. 0,252,504. In particular, methods for thepreparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salttrihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat. No.4,922,007, respectively.

The pharmaceutical compositions containing the bisphosphonic acids andsalts set forth in the patents listed above have the disadvantage thatthe active ingredients are released from the medications almostinstantaneously in the upper gastrointestinal tract causing esophagealdiscomfort and ulceritis. Thus, the medications have to be taken onarising for the day and at least 30 minutes before the first food,beverage or medication with a full glass (200 ml) of plain water only.The patients are advised to sit upright for about 30 minutes afteringestion of the medication and until their first food of the day.Patients are instructed not to take medication at bedtime or beforearising for the day. See Physician's Desk Reference (U.S.) ProductInformation, 1999, p. 1798.

Several problems have been noted in the preparation of tabletformulations comprising bisphosphonic acid active ingredients, and inparticular with enteric coated forms of these active ingredients. Forexample, U.S. Pat. No. 5,431,920 points out that “standard methods fortablet formulation of bisphosphonic acids suffer from seriousdifficulties.” Thus, particular dry mix formulations are required whenformulating tablets from these active ingredients. In addition, thissame patent points out that “[e]nteric coated dosage forms can sufferfrom stability problems as a result of interactions between the activedrug and the acidic enteric coatings.”

The present invention solves these problems by providing dosage forms ofbisphosphonic acids that do not require formulation into tablets. Thedosage forms of the present invention also have improved stability ascompared to prior art formulations.

SUMMARY OF THE INVENTION

In summary, the invention is related to pharmaceutical compositionscomprising bisphosphonic acids and salts thereof, their preparation andmethod of use. More specifically, the invention is related topharmaceutical compositions comprising alendronic acid and relatedcompounds or salts thereof surrounding an inert core, which is coveredwith a seal coating which is further covered with an enteric coating.

The invention provides pharmaceutical compositions for the treatment ofdisorders caused by the abnormal dissolution or deposition of calciumsalts. The pharmaceutical compositions of the invention comprise aninert core, an active coating containing at least one bisphosphonic acidor salt thereof surrounding the inert core, a seal coating surroundingthe active coating, and an enteric coating around the seal coating.Preferred bisphosphonic acids are selected from the group consisting of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,N-methyl-4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid,4-(N,N-dimethylamino)-1-hydroxybutyl-idene-1,1-bisphosphonic acid,3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,3-(N,N-dimethylamino)-1-hydroxy-propylidene-1,1-bisphosphonic acid,1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid,and 4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine. Alendronicacid is a particularly preferred acid and alendronate sodium trihydrateis a particularly preferred salt. Other preferred salts includeetidronate, clodronate, pamidronate, and ibandronate. The compositionspreferably comprise from about 4% to about 40% by weight of at least onebisphosphonic acid or salt.

Typical enteric coatings for use in the invention include one or more ofhydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose acetylsuccinate, cellulose acetate phthalate, polyvinyl acetate phthalate, andmethacrylic acid-methyl methacrylate copolymers.

The active ingredient is coated onto an inert core, such as nonpareilsin the form of sugar beads or sugar/starch beads, to form the activecore. The composition may further contain pharmaceutically acceptableexcipients, diluents, binders, solubilizers, lubricants, disintegrants,etc. In particular, the active core is formed by applying an activecoating to the inert core. The active coating comprises the activeingredient and may further comprise a polymer. Preferred polymersinclude hydroxypropyl methicellulose, hydroxypropyl cellulose andpolyvinyl pyrrolidone Compositions according to the invention may be inthe form of enteric coated beads in gelatin capsules or Peltabs, and theinvention further provides a process for preparing the claimedcompositions in these forms. The gelatin capsules or Peltabs maythemselves be coated with an enteric coating. The inventive compositionsare preferentially released in the lower gastrointestinal tract uponingestion and thus avoid the disadvantages described above for the priorart.

The invention also provides methods for the treatment of disorderscaused by the abnormal dissolution or deposition of calcium salts bytreating a patient in need of such treatment with a therapeuticallyeffective amount of the inventive compositions. Disorders caused by theabnormal dissolution or deposition of calcium salts that may be treatedby the compositions of the invention include osteoporosis,osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, cholelithiasis, nephrolithiasis, urinary calculus,arteriosclerosis, arthritis, bursitis, neuritis and tetany. Thecompositions are particularly useful for the treatment of osteoporosis.

The above objectives and advantages of the invention are illustrative,and not exhaustive, of those which can be achieved by the invention. Theexamples presented herein are non-limiting. Thus, these and otherobjectives and advantages of the invention will be apparent from thedescription herein, both as embodied herein and as modified in view ofany variations which will be apparent to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition comprisingfrom about 4% to about 40% by weight of at least one 1,1-bisphosphonicacid or salt thereof as an active ingredient. The 1,1-bisphosphonic acidis preferably selected from the group consisting of:

-   -   4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    -   N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;    -   4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic        acid;    -   3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;    -   3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic        acid;    -   1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic        acid; and    -   4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine.

In the present invention, the preferred active ingredient is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, i.e. alendronicacid, and, more preferably, its monosodium salt trihydrate, alendronatesodium trihydrate. Other bisphosphonic acids or salts thereof may beused as well, including, for example, etidronate, clodronate,pamidronate or ibandronate. Suitable salts for use in the presentinvention may be formed with, for example, alkali metals, amines andalkanol amines. Salts may be formed by reacting the acid with an alkalimetal hydroxide (e.g. LiOH, NaOH), alkali metal carbonates (e.g.Na₂CO₃), lower alkylamines (e.g. methylamine), lower alkanolamines (e.g.ethanolamine, diethanolamine, triethanolamine) or quaternary ammoniumsalts (e.g. tetramethylammonium hydroxide).

The invention provides pharmaceutical compositions for oraladministration substantially comprising an inert core, an active coatinghaving at least one bisphosphonic acid or salt thereof surrounding theinert core, a seal coating surrounding the active coating and an acidresistant coating (the “enteric coating”) surrounding the seal coating.The present invention thus is able to resist the acidic environment ofthe stomach and avoid the release of the medication in the uppergastrointestinal tract where it may cause esophageal or stomachdiscomfort or ulceritis. Accordingly, the disadvantages described abovefor the prior art compositions are overcome by the present invention.

The active core may be achieved by any process known in the art ofmaking pellets, for example, extrusion spheronization, centrifugalcoating, wurster coating, and others. According to the invention, anactive core may be formed on an inert core, such as non-pareils, byapplying an active coating comprising at least one bisphosphonic acid orsalt. The bisphosphonic acids or salts may be mixed withpharmaceutically acceptable components, such as binding agents,solubilizers, lubricants, diluents, disintegrants, etc., prior toforming the active coating on the inert core. In addition, thebisphosphonic acid or salt thereof may be applied with a polymer to forma polymer film. Preferred polymers are hydroxypropyl methylcellulose,hydroxypropyl cellulose and polyvinyl pyrrolidone.

The active core containing the bisphosphonic acid or salt may be coatedwith a hydrophilic polymer known in the art, i.e. a seal coating. Asuitable seal coating may comprise, for example, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), shellac, cellulose gums and xanthan gums. The sealcoated active core is then further coated with an enteric coating.

A wide variety of conventional enteric coatings may be employed in thepresent invention, including, for example: cellulose acetate phthalate;hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl celluloseacetyl succinate; polyvinyl acetate phthalate; copolymerized methacrylicacid/methacrylic acid methyl esters, such as Eudragit L 12.5, Eudragit L100 55, and Eudragit S 100; and mixtures thereof. The enteric coatingmay further contain conventional plasticizers, pigments and/ordispersants, including, for example, polyethylene glycols, triacetin,triethyl citrate, Citroflex and dibutyl sebacate.

The enteric coating may be applied in any suitable manner known in theart, such as, for example, by using a Wurster coater. When applied, theenteric coating may be in the form of an aqueous dispersion in water orother dispersing medium, or in the form of a solution. If the entericcoating is applied in the form of a dispersion or solution, it ispreferred that the dispersion or solution be treated with an alkaliprior to applying the enteric coating to the active core in order toneutralize at least part of any free acid content. The alkali may be,for example, a carbonate or a hydroxide of sodium, potassium, magnesiumor calcium.

Bisphosphonic acids and salts thereof that may be incorporated into theformulations according to the present invention have been found to beuseful in treating a variety of disorders in mammals. These disordersgenerally relate to abnormalities of calcium or phosphate metabolicpathways and particularly to the abnormal dissolution or deposition ofcalcium salts. Disorders that have been found to be treatable usingbisphosphonic acids and salts include osteoporosis, osteodystrophy,Paget's disease, myositis ossificans, Bechterew's disease,cholelithiasis, nephrolithiasis, urinary calculus, arteriosclerosis,arthritis, bursitis, neuritis and tetany. The pharmaceuticalcompositions prepared according to the invention are particularly usefulfor the treatment of osteoporosis.

The dosages of the compounds may be variable and depend on theparticular condition to be treated and other factors including theseverity of the illness, duration of treatment and the identity of theparticular compounds being used. Effective dosages preferably range fromabout 0.05 to about 500 mg/kg body weight/day and more preferably fromabout 1 to about 50 mg/kg/day. The dosage is typically administered in 4individual doses. After initial treatment with a relatively high dose,it may be necessary to continue treatment at a lower dose to maintainthe beneficial effects of the compounds.

Pharmaceutical compositions according to the present invention mayfurther comprise one or more additives. Examples of particularly usefuladditives include diluents to aid dissolution of the pharmaceuticallyactive ingredient and lubricants to aid flow of the active ingredientduring manufacture. The diluent may be, for example, lactose. Thelubricant may be, for example, magnesium stearate and/or talcum. It willbe appreciated that the pharmaceutical compositions of the invention mayalso contain any one or more other additives conventionally used in theformulation of pharmaceutical compositions. Additives may includeexcipients known in the art of manufacturing capsules and Peltabs, suchas lactose, microcrystalline cellulose, dicalcium phosphate, starch,sugar, and disintegrants (e.g., starch and derivatives of starch, sodiumcarboxy methyl cellulose and its derivatives, and crospovidone).

The pharmaceutical composition of the present invention may take theform of Peltabs or pellets in a capsule. The disadvantages of formingtablets containing bisphosphonic acids described in the prior art arethus avoided. A further advantage of the invention is that the capsuleor Peltab can break down in the stomach releasing the enteric coatedbeads which can then move freely into the lower gastrointestinal tract.This avoids problems associated with a tablet sitting in the stomachuntil the digestion of food opens the pyloric sphincter and the tabletpasses into the duodenum. In addition, the use of small beads decreasesthe risk of large local concentrations of the active ingredients cominginto contact with mucosal or epithelial tissue.

The relative release rate of the active ingredient from the entericcoated beads may be varied by changing one or more of (a) the activeingredient, (b) the composition and thickness of the enteric coating;(c) the composition and thickness of the seal coating; (d) the amount ofactive ingredient in individual beads; and (e) the size of the beads.Thus, the composition may be adjusted to allow release in the smallintestine, the large intestine or throughout the intestinal tract. Inaddition, release rates can be controlled by applying an additionalenteric coating over the gelatin capsule or over the Peltab after itsformulation.

According to one embodiment of the present invention, the active corecomprises an inert core, such as nonpareils provided in the form ofsugar beads or sugar/starch beads, as well as the bisphosphonic acid orsalt. Inert cores may be approximately 0.6 mm in diameter and arepreferably from about 0.2 mm to about 1.0 mm in diameter. Thebisphosphonic acid or salt thereof is loaded onto each of a plurality ofthe inert cores as an active coating. The bisphosphonic acid or salt mayalso be mixed with one or more additives before being loaded onto theinert cores. The additives may include, for example, a solubilizerand/or a lubricant. The bisphosphonic acid or salt (together with anyadditives) can be sprayed onto the inert core with a binder in acentrifugal coating apparatus. A polymer, such as HPMC, HPC or PVP maybe applied in conjunction with the application of the active ingredientto form the active coating as a polymer film. A seal coating is appliedaround the active core, and the enteric coating is then provided aroundthe seal coating on each of the active cores. This embodiment of theinvention is particularly useful when the capsule form of thepharmaceutical composition is desired. A plurality of pellets containingthe bisphosphonic acid or salt loaded on inert cores and coated withseal coatings and enteric coatings may be included in a capsule shell.

Another embodiment of the present invention is particularly useful ifthe Peltab form of the pharmaceutical composition is desired. In thisembodiment, the active cores of the pellets comprise nonpareils providedin the form of sugar beads or sugar/starch beads onto which thebisphosphonic acid or salt has been loaded as described above. A sealcoating is applied around the active core of each of the pellets, andthe enteric coating provided around the seal coating on each of theactive cores. A plurality of these pellets, which may be combined withone or more conventional additives, such as disintegrants and binders,may then be compressed into tablets generally known as Peltabs.

The following examples illustrate the invention. In each case, theactive drug is a bisphosphonic acid or salt thereof, unless indicatedotherwise. While sucrose (sugar) is the illustrated binding agent, otherbinding agents, such as polyvinylpyrrolidone, shellac or xanthan gum,may be used instead. Examples 1 through 3 present general examples ofthe preparation of pharmaceutical compositions containing bisphosphonicacids or salts thereof. Although, in principal, any bisphosphonic acidor salt may be used in the formulations, the formulations areparticularly useful for preparing pharmaceutical compositions comprisingalendronate sodium trihydrate.

EXAMPLE 1

Capsules:

A plurality of pellets containing the active drug are prepared from thefollowing materials:

Core: Nonpareil seeds 95 mg Active drug 13.03 mg Sucrose 31.97 mg Cornstarch 32 mg Talcum 10 mg HPMC 1 mg 183 mg Water: as required Sealcoating: HPMC 7.2 mg Talc 1.4 mg Propylene glycol 1.4 mg 10 mg Water: asrequired Isopropyl alcohol: as required Enteric coating: Eudragit L100-55 22.50 mg Sodium hydroxide 0.320 mg Triethyl citrate 2.270 mg Talc22.50 mg Titanium dioxide 2.18 mg Aerosil 0.23 mg 50.00 mg Water: asrequired

The active drug, the sucrose, the corn starch and the talcum are blendedthoroughly to yield a dusting powder. The nonpareil seeds are loadedinto a centrifugal coater and then coated with the dusting powder whilespraying the HPMC (hydroxypropyl methyl cellulose) solution. Thisprocedure results in the production of a plurality of discrete pelletscontaining the active ingredient. The pellets so obtained are driedusing conventional tray dryers or fluid bed dryers up to an outlettemperature of 45° C. These pellets are then seal coated using HPMCsolution and further enteric coated in a suitable Wurster coater. Thepellets are then included in a capsule shell.

EXAMPLE 2

Capsules:

A plurality of pellets containing the active drug are prepared from thefollowing materials:

Core: Nonpareil seeds 95 mg Active drug 13.03 mg Sucrose 31.97 mg Cornstarch 32 mg Talcum 10 mg HPMC 1 mg 183 mg Water: as required Sealcoating: HPMC 7.2 mg Talc 1.4 mg Propylene glycol 1.4 mg 10 mg Water: asrequired Isopropyl alcohol: as required Enteric coating: Eudragit L100-55 18.00 mg Sodium hydroxide 0.25 mg Triethyl citrate 1.81 mg Talc18.00 mg Titanium dioxide 1.75 mg Aerosil 0.19 mg 40.00 mg Water: asrequired.

The active drug, the sucrose, the corn starch and the talcum are blendedthoroughly to yield a dusting powder. The nonpareil seeds are loadedinto the centrifugal coater and then coated with the dusting powderwhile spraying the HPMC solution. This procedure results in theproduction of a plurality of discrete pellets containing the activeingredient. The pellets so obtained are dried using conventional traydryers or fluid bed dryers up to an outlet temperature of 45° C. Thesepellets are then seal coated using HPMC solution and further entericcoated in a suitable Wurster coater. The pellets are then included in acapsule shell.

EXAMPLE 3

Peltabs:

A plurality of particles containing the active drug are prepared fromthe following materials:

Core: Nonpareil seeds 110.07 mg Active drug 13.03 mg Sucrose 35.90 mgCorn starch 21.00 mg Talcum 2 mg HPC-L Klucel 1 mg 183 mg Water: asrequired Seal coating: HPMC 7.2 mg Talc 1.4 mg Propylene glycol 1.4 mg10 mg Water: as required Isopropyl alcohol: as required Enteric coating:Eudragit L 100-55 22.50 mg Sodium hydroxide 0.320 mg Triethyl citrate2.270 mg Talc 22.50 mg Titanium dioxide 2.18 mg Aerosil 0.23 mg 50.00 mgWater: as required Microcrystalline cellulose 50 mg Croscarmellosesodium 7 mg 57.00 mg

The active drug, the sucrose, the corn starch and the talcum are blendedthoroughly to yield a dusting powder. The nonpareil seeds are loadedinto the centrifugal coater and then coated with the dusting powderwhile spraying the HPC-L Klucel (hydroxypropyl cellulose) solution. Thisprocedure results in the production of a plurality of discrete pelletscontaining the active ingredient. The pellets so obtained are driedusing conventional tray dryers or fluid bed dryers up to an outlettemperature of 45° C. The pellets are then seal coated using the HPMCsolution and further enteric coated in a suitable Wurster coater. Thepellets are then suitably diluted with binders and disintegrants andcompressed by conventional means to form tablets.

The embodiments and non-limiting examples illustrated and discussed inthis specification are intended only to teach those skilled in the artthe best way known to the inventors to make and use the invention.Nothing in this specification should be considered as limiting the scopeof the present invention.

1. A pharmaceutical composition for the treatment of a disorder causedby the abnormal dissolution or deposition of calcium salts comprising:an inert core, an active coating surrounding the inert core, a sealcoating surrounding the active coating, and an enteric coating aroundsaid seal coating; wherein the active coating comprises at least onebisphosphonic acid or salt thereof.
 2. The composition according toclaim 1, wherein the at least one bisphosphonic acid is selected fromthe group consisting of: 4-Amino-1-hydroxybutylidene-1,1-bisphosphonicacid; N-Methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-Dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;3-Amino-1-hydroxypropylidene-1,1-bisphosphonic acid;3-(N,N-Dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-Hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;4-(Hydroxymethylene-1,1-bisphosphonic acid)-piperidine; and saltsthereof.
 3. The composition according to claim 1, wherein the at leastone bisphosphonic acid is alendronic acid.
 4. The composition accordingto claim 1, wherein the at least one bisphosphonic acid or salt thereofis selected from the group consisting of alendronate sodium trihydrate,etidronate, clodronate, pamidronate, and ibandronate.
 5. The compositionaccording to claim 1, wherein the composition comprises from about 4% toabout 40% by weight of the at least one bisphosphonic acid or saltthereof.
 6. The composition according to claim 1, wherein the sealcoating comprises one or more hydrophilic polymers selected from thegroup consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, shellac, cellulose gum and xanthangum.
 7. The composition according to claim 1, wherein the entericcoating is selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropyl cellulose acetyl succinate,cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylicacid-methyl methacrylate copolymers, and mixtures thereof.
 8. Thecomposition according to claim 7, wherein the methacrylic acid-methylmethacrylate copolymer is an anionic polymer based on methacrylic acidesters.
 9. The composition according to claim 1, wherein the inert corecomprises sugar beads or sugar/starch beads.
 10. The compositionaccording to claim 1, wherein the active coating further comprises atleast one of a solubilizer and a lubricant.
 11. The compositionaccording to claim 1, wherein the active coating comprises a polymerfilm comprising a mixture of at least one bisphosphonic acid or saltthereof and a polymer.
 12. The composition according to claim 11,wherein the polymer is selected from the group consisting ofhydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinylpyrrolidone.
 13. The composition according to claim 1, furthercomprising a binder.
 14. A capsule or Peltab comprising a plurality ofpellets each of which comprises a composition according to claim
 1. 15.The composition according to claim 1, wherein the composition releasesthe at least one bisphosphonic acid or salt thereof only in the lowergastrointestinal tract of a human or animal upon ingestion.
 16. Thecomposition according to claim 1, wherein the disorder caused by theabnormal dissolution or deposition of calcium salts is selected from thegroup consisting of osteoporosis, osteodystrophy, Paget's disease,myositis ossificans, Bechterew's disease, cholelithiasis,nephrolithiasis, urinary calculus, arteriosclerosis, arthritis,bursitis, neuritis and tetany.
 17. The capsule or Peltab of claim 14,further comprising an enteric coating over said capsule or Peltab.
 18. Amethod for treating a disorder caused by the abnormal dissolution ordeposition of calcium salts comprising: providing a pharmaceuticalcomposition; and administering an effective dose of the pharmaceuticalcomposition to a person in need thereof; wherein the pharmaceuticalcomposition comprises an inert core, an active coating surrounding theinert core, a seal coating surrounding the active coating, and anenteric coating around said seal coating; and wherein the active coatingcomprises at least one bisphosphonic acid or salt thereof.
 19. Themethod according to claim 18 wherein the at least one bisphosphonic acidis selected from the group consisting of:4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-Methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-Dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;3-Amino-1-hydroxypropylidene-1,1-bisphosphonic acid;3-(N,N-Dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-Hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;4-(Hydroxymethylene-1,1-bisphosphonic acid)-piperidine; and saltsthereof.
 20. The method according to claim 18, wherein the at least onebisphosphonic acid is alendronic acid.
 21. The method according to claim18, wherein the at least one bisphosphonic acid salt is selected fromthe group consisting of alendronate sodium trihydrate, etidronate,clodronate, pamidronate, and ibandronate.
 22. The method according toclaim 18, wherein the disorder caused by the abnormal dissolution ordeposition of calcium salts is selected from the group consisting ofosteoporosis, osteodystrophy, Paget's disease, myositis ossificans,Bechterew's disease, cholelithiasis, nephrolithiasis, urinary calculus,arteriosclerosis, arthritis, bursitis, neuritis and tetany.